Glioblastoma multiforme (GBM) is the most aggressive class of brain tumors, making up 17% of all primary brain tumors in the United States, with an incidence of 3.17 cases per 100,000 persons/year (CBTRUS. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004-2006, Hinsdale, IL: Central Brain Tumor Registry of the United States; 2010). Although they generally do not metastasize out of the brain, they do spread aggressively through normal brain tissue. The current five- and ten-year survival rates for GBM patients are 4,5% and 2.7%, respectively (Id.).
The current treatment for GBMs is an intense combination of surgical resection or debulking, radiotherapy and chemotherapy. The most effective chemotherapy drug is temozolomide (TMZ, also known as TEMODAR™), which is an alkylating agent that is taken orally and readily penetrates the blood-brain barrier (Ostermann et al., Clin Cancer Res 2004; 10: 3728-36). This aggressive treatment increases the two-year survival rate for GBM patients from 10.4% with radiotherapy alone, to 26.5% (Stupp et al., N Engl J Med 2005; 352: 987-96). Cells that escape radiotherapy- and chemotherapy-induced cell death eventually re-enter the cell cycle and contribute to local tumor recurrence. Despite advances in chemotherapy regimens, the median progression-free survival, which measures the time until tumor recurrence, is 6.9 months, and the median overall survival is 14.6 months with temozolomide and radiotherapy (Stupp et al., N Engl J Med 2005; 352: 987-96). Hence, there is a dire need to target the cells that evade current treatments.